1. Field of the Invention
The present invention relates generally to methods and compositions which are useful in selectively introducing pharmaceutical or diagnostic agents into abnormal brain tissue. More particularly, the present invention involves methods and compositions which selectively increase the permeability of the blood-brain barrier in abnormal brain tissue to provide for directed delivery of pharmaceutical or diagnostic agents to such abnormal tissue.
2. Description of the Related Art
The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are is numerically referenced and grouped in the appended bibliography.
Capillaries within the brain include a barrier which prevents the delivery of many pharmaceutical agents to the brain. This blood-brain barrier (BBB) is present in both normal and abnormal brain tissue. The treatment of brain tissue abnormalities, such as tumors, require that the neuropharmaceutical agent be preferentially directed to the abnormal tissue. Accordingly, there has been a great deal of interest in developing techniques which are capable of opening the blood-brain barrier to allow transport of neuropharmaceutical agents to the brain (1, 2, 3, 4 and 5). None of these methods, however, are capable of selectively opening the blood-brain barrier only in the abnormal brain while leaving the blood-brain barrier in the normal brain intact.
In previous studies, it was demonstrated that intracarotid infusion of leukotriene C.sub.4 (LTC.sub.4) selectively increases the permeability in brain tumor capillaries without affecting the permeability in normal brain capillaries (6-9). The effect of LTC.sub.4 on brain tumor capillaries is, however, limited to small molecules and it can only slightly increase the permeability of those small molecules in abnormal brain tissue. Accordingly, LTC.sub.4 does not significantly increase the delivery of some water soluble drugs to brain tumors (10-13).
Bradykinin is a naturally occurring peptide formed from a plasma protein, high molecular weight kininogen by the action of kallikrein. Bradykinin is a very powerfull vasodilator that increases capillary permeability. In addition, bradykinin constricts smooth muscle and stimulates pain receptors. Bradykinin may reduce cerebral blood flow (14, 15) and in high doses will induce breakdown of the normal blood-brain barrier (16). U.S. Pat. No. 5,112,596 discloses the intravenous administration of bradykinin and bradykinin agonists to provide a general increase of blood-brain barrier permeability.
U.S. Pat. Nos. 5,434,137 and 5,527,778 disclose the use of bradykinin and bradykinin analogs to selectively increase the permeability of abnormal brain tissue capillaries to both low and high molecular weight neuropharmaceutical and neurodiagnostic agents. The methods disclosed in these patents utilize intracarotid artery infusion of low doses of bradykinin or a bradykinin analog to achieve the desired selective delivery of neuropharmaceutical agents to abnormal brain tissue. The mechanism by which bradykinin achieves such selective action on abnormal brain tissue capillaries has not been well understood.
In view of the above, there is a continuing need to develop methods for selectively opening abnormal brain tissue capillaries in order to allow selective passage of neuropharmaceutical agents into abnormal brain tissue without increasing the permeability of the normal blood-brain barrier.